Intermolecular Aza-Wacker Coupling of Alkenes with Azoles by Photo-Aerobic Selenium-π-Acid Multicatalysis

Herein, the intermolecular, photoaerobic aza-Wacker coupling of azoles with alkenes by means of dual and ternary selenium-π-acid multicatalysis is presented. The title method permits an expedited avenue toward a broad scope of N-allylated azoles and representative azinones under mild conditions with broad functional group tolerance, as is showcased in more than 60 examples including late-stage drug derivatizations. From a regiochemical perspective, the protocol is complementary to cognate photoredox catalytic olefin aminations, as they typically proceed through either allylic hydrogen atom abstraction or single electron oxidation of the alkene substrate. These methods predominantly result in C–N bond formations at the allylic periphery of the alkene or the less substituted position of the former π-bond (i.e., anti-Markovnikov selectivity). The current process, however, operates through a radical-polar crossover mechanism, which solely affects the selenium catalyst, thus allowing the alkene to be converted strictly through an ionic two-electron transfer regime under Markovnikov control. In addition, it is shown that the corresponding N-vinyl azoles can also be accessed by sequential or one-pot treatment of the allylic azoles with base, thus emphasizing the exquisite utility of this method.


■ INTRODUCTION
Azoles represent a structural motif frequently found in biologically and pharmaceutically active compounds. 1Due to the industrial significance of this heterocycle class, substantial efforts were invested into method development and strategical concepts for their bespoke and diversified syntheses. 2In this context, 3 electrophilic allylations of azoles were shown to offer an expedited avenue toward valorized building blocks and synthetic intermediates for established pharmaceuticals, drug leads, and agrochemicals. 4The direct redox-coupling of 1,2-dior higher substituted alkenes to azoles without any prefunctionalization 5 of either reactant provides a streamlined, highly redox economic 6 avenue to customized target structures.However, a severe challenge associated with such enterprises arises from regiochemical considerations.More concretely, nonpolar, internal alkenes offer up to 4 positions at which the C−N σ-bond coupling can take place, depending on the nature of the activation principle and substitution pattern around the alkene (Scheme 1a, paths a,b: C−N bond in position 1 or 4 with the double bond fixed within positions 2 and 3; paths c,d: C−N bond in position 2 or 3 with concomitant transposition of the double bond terminating at position 4 or 1, respectively).
C−H σ-bond activations via hydrogen atom transfer (HAT) can result in the functionalization of each position from 1 to 4 (Scheme 1a, path a or b), while direct electrophilic π-bond activations are restricted to C−N couplings in position 2 or 3 (Scheme 1a, path c or d).So far, only a small number of suitable synthetic methods have been reported that allow for the regioselective allylation of azoles.Sporadic early examples of such C−N couplings predicated on the use of, in part, corrosive oxidants, such as N-halosuccinimides, peroxides, and benzoquinones, were restricted to alkene substrates with specific substitution patterns (e.g., terminal or π-conjugated).5a−c In 2022, Gevorgyan et al. reported a Pd-photoredox hybrid-catalytic C−N coupling to construct a broad series of allylated amines, including two azoles, from simple alkenes via allylic HAT.The protocol relied on the use of customized aryl bromides as terminal oxidants to generate aryl radicals as key HAT acceptors (Scheme 1b, top).The regiochemical preference for C1 functionalization (Scheme 1a, path a) was governed by thermodynamic and steric substrate control.5d A complementary approach was recently reported by Lei, Cai, and co-workers, who showed that N-allylation of azoles can be accomplished through dual photoredox/cobalt catalysis (Scheme 1b, bottom).5e The protocol is mechanistically reminiscent of earlier work by Yoon et al. on Cu-mediated, photoredox catalytic allylations of N-and O-nucleophiles 7 and accordingly shows strong anti-Markovnikov regioselectivity in preference of position 3 (Scheme 1a, path d).Despite the promising achievements made so far in the context of azole allylations, protocols that are generally suitable for 1,2disubstituted alkenes and that display high electronic or, in the case of 1,1,2-trisubstituted alkenes, Markovnikov regioselectivity remain yet to be established.
A promising alternative to existing methods on azole allylations may lie in the implementation of selenium-π-acid catalysis. 8In the past, this technique has shown unique abilities to control regioselectivity via dynamic covalent π-bond activation, which has been successfully applied in the vinylic-, 9 allylic-, 10,11 and 1,2-difunctionalization 12 of olefins with a vast panoply of nucleophiles.A seminal example of selenium-πacid-catalyzed intermolecular C−N couplings between simple alkenes and N-fluorobenzenesulfonimide (NFSI) was already reported in 2013. 13In these reactions, the actual sulfonimide nucleophile was released in situ during the catalytic cycle.Subsequently, various conceptually related allylic and vinylic aminations were reported, including an interesting electrophilic N-vinylation of pyridines.9d Most of these procedures predicate on the use of halogen oxidants and tolerate only oxidationinsensitive N-nucleophiles.A notable further development in this field was demonstrated by Michael et al., who elaborated a selenium-catalyzed ene reaction using hypervalent iodine reagents as terminal oxidants.11c−j, 14 The protocol displayed high substrate-based regiocontrol and was found suitable for mono-to tetrasubstituted alkenes but was specific to primary sulfonamide and carbamate coupling partners for the alkenes.
The abovementioned state of affairs in selenium-π-acid catalysis already indicates that its synthetic potential is far from being exhaustively exploited.For instance, our group has previously shown that the scope of suitable nucleophiles can be markedly enhanced when resorting to ambient air as a mild and compatible terminal oxidant. 15The implementation of air as a reactant was accomplished by the merger of photoredox and selenium-π-acid catalysis, enabling the coupling of various nucleophiles such as carboxylic acids, 15a,b hydrogen phosphates, 15c alcohols, 15d and sulfonamides 15f,g to simple alkenes through a dual catalytic radical-polar crossover mechanism. 16gainst this background, we posited that this technique might also prove suitable for azole nucleophiles, provided that the envisioned heteroarenes would exhibit sufficient compatibility with our photoaerobic reaction conditions.As a result of these considerations, we present herein the first photoaerobic selenium-π-acid-catalyzed aza-Wacker coupling of alkenes with N-heterocycles, exemplified with a broad series of azoles and selected azinones (Scheme 1c).The title protocol shows strong, alkene-based electronic regiocontrol (including Markovnikov selectivity for mono-and trisubstituted alkenes) and high functional group tolerance, even in complex molecular architectures.In addition to allylations, the corresponding vinylation products can also be accessed in high yields through eventual exposure of the allylated azole intermediates to a base, which is a testament to the marked flexibility of our method.

■ RESULTS AND DISCUSSION
At the outset, 3 equiv of (E)-hex-3-enoic acid ethyl ester (1a) were exposed to 4-chloropyrazole (2a) in the presence of 5 mol % 2,4,6-tris(4-methoxyphenyl)pyrylium tetrafluoroborate (TAPT) and 10 mol % (PhSe) 2 under air and 448 nm irradiation in dichloroethane (DCE), yielding product 3a in 65% along with 11% vinylic isomer 3a' (Table 1, entry 1, 3a:3a' = 6:1).Under these conditions, no electrophilic selenation of the azole core was observed. 17While chloroform also provided a total yield of 76% for isomers 3a and 3a' with a slightly lower isomeric ratio (entry 2, 3a:3a' = 5:1), other solvents such as acetonitrile, acetone, and toluene gave inferior results (entries 3−5).From previous studies on asymmetric aza-Wacker cyclizations we learned that disulfide cocatalysts can accelerate the overall reaction rate and suppress side reactivity.15f Mechanistic investigations indicated that disulfides serve two purposes: (1) they function as electron−hole shuttles between the excited photoredox catalyst and the selenium cocatalyst, and (2) they accelerate the final step in the catalytic cycle, namely the β-elimination of the product from the selenium catalyst.15g Accordingly, we added 5 mol % (4-ClPhS) 2 to the reaction mixture and ran the reaction for 21 h on an 1.0 mmol scale (for scale-up results, see the Supporting Information), which resulted in a comparable total yield of 78% but with a markedly improved isomeric ratio of 13:1 (entry 6).A similar isomeric ratio improvement was observed when alkene 2a was used as the limiting reagent in the presence of 3 equiv of pyrazole 1a (entry 7, 3a:3a' = 14:1).The addition of the disulfide cocatalyst to the latter conditions further improved the isomeric ratio of the product to 25:1, albeit with a slight decrease in total yield (entry 8).Control experiments showed that TAPT, (PhSe) 2 , light, and air are crucial components in the reaction (entries 9−12).
With an empirically optimized set of reaction conditions in hand, the substrate scope was examined next by initially varying the alkene coupling partner (Scheme 2).For this purpose, several, in part, acid-sensitive groups were incorporated into the backbone of target 3. Installation of various polar groups next to position 2 (3c-3k) had no apparent negative impact on the yield, which ranged between 53 and 99%.Also, regioisomer 3 was consistently preferred over 3′ in all of these reactions, with a minimum ratio of 7:1 prior to purification and 13:1 after it.These results already show that common functional groups such as halide, cyanide, arene, ether, acetal, and ester moieties are well tolerated.This positive trend continued to hold true for the diester series 3l to 3r, for which an average yield of 92% was obtained without any indication for the formation of isomer 3'.To analyze the tolerance of the title protocol toward the presence of various π-bonds and strained rings, monoesters 1s to 1y (see the Supporting Information for details) were converted to their respective aza-Wacker coupling products 3s-y.Particularly noteworthy from this series are the results of compounds 3w to 3y, as both the alkyne and the secondary Z-alkene group remained largely intact during the catalytic conversion of the coexisting E-alkene.We interpret this outcome, on the one hand, as a result of −I effects (3x and 3y) exerted by the proximal oxygen atoms and, on the other hand, as a consequence of the high scharacter of the C-atoms in the alkyne, which presumably destabilizes the corresponding selenirenium ion relative to the competing seleniranium ion from the alkene.This kind of chemoselectivity (i.e., alkene vs alkyne) has been observed previously 18 in related selenium-π-acid-catalyzed reactions and bears testament to the exquisite utility of this methodology in polyfunctional settings.
Switching to other electron-withdrawing groups (e.g., malonyl, sulfonyl, nitrile, and phosphonate) or different degrees of olefin substitution within the substrates or products provided access to compounds 3z to 3aj in yields between 51 and 84% (avg.= 69%; median = 67%).These results were next contrasted with those obtained from alkenes being void of any electron-withdrawing groups (Scheme 2b).As anticipated, the yields of azole coupling products 3ak-aq are on average 23 percentage points lower (34−56%) compared to the 3z-aj series, even with the addition of cocatalyst (4-ClPhS) 2 .This observation correlates well with several mechanistic studies from our laboratories, which suggest that either the final step in the multicatalytic cycle, i.e., the β-elimination of the product from the selenium catalyst, 15,19 or the preceding photooxidation of the selenium residue 15b can be rate limiting.The missing electronic influence of any electron-withdrawing groups (EWG) in the case of nonpolar alkenes 2ak-2ao is suspected to slow down β-elimination considerably, opening pathways for probably yield-diminishing side reactions such as the Schenck-ene oxidation. 15,20Notably, the current method shows significant preference for the formation of Markovnikov products, 21 which complements existing protocols on photoredox catalytic amination reactions of nonpolar alkenes proceeding through radical ionic π-bond activations, as they typically result in preferential formation of anti-Markovnikov regioisomers (Scheme 1a, path d).5e,7 At this stage, we tested an extended panoply of azoles and a few azinones as coupling partners to alkenes 1a and diethyl (E)-hex-3-enedioate 1c (Scheme 2c).Overall, our method provided for all tested heterocycles relatively consistent results with yields averaging around 59% (median = 61%) for the monoester series 3ar-aw (derived from 1a) and 63% (median = 56%) for the diester series 3ax-bj (derived from 1c).As in all cases before, functional groups such as halides, esters, and amides proved to be compatible with the reaction conditions.In addition, no sign of direct heteroarene selenation was observed. 17Given the robust functional group tolerance of the title procedure, we applied it to late-stage derivatizations of biologically active compounds and drug analogs (Scheme 3a).More concretely, testosteryl ester 1ap was subjected to the title conditions and gave access to its pyrazolated and benzotriazolated (via N 1 ) products 3bk and 3bl in 74% (r.r.= 11:1) and 58% yield (r.r.>49:1), respectively.Commercially available irbesartan (2u) and stanozolol (2v), each decorated with tetrazole and pyrazole moieties, respectively, were readily converted under optimized conditions to give derivatives 3bm and 3bn in 35 and 36% yields, respectively.As indicated earlier (Table 1), an attack of the azole in position 3 exclusively resulted in the formation of vinylic products 3′, presumably because of the −I effect of the azole group (i.e., increased acidity of the C−H bond in position 3).We posited that exposure of coupling products 3 to basic conditions would result in complete isomerization toward vinylic isomers 3″ Conditions: 4-Chloropyrazole (2a, 0.30 mmol, 1.0 equiv), (E)-hex-3-enoate 1a (3.0 equiv), TAPT (5 mol %), (PhSe) 2 (10 mol %), solvent (4 mL), 448 nm irradiation, air, and 19 °C.b Yield determined by 1 H NMR spectroscopy using 1,4-dimethoxybenzene as an internal standard.Isolated yield in parentheses.c (4-ClPhS) 2 (5 mol %) added.d Pyrazole 2a (1.0 mmol, 1.0 equiv), alkene 1a (3.0 equiv), and DCE (5 mL).e Alkene 1a (1.0 mmol, 1.0 equiv), pyrazole 2a (3.0 equiv), and DCE (5 mL).Control experiments were performed under unaltered conditions except for the parameters indicated as follows: f without irradiation.g without (PhSe) 2 , h without TAPT, i N 2 instead of air.For further details, see the Supporting Information.
(Scheme 3b).This turned out to be true since the exposure of coupling products 3a, 3w, and 3av to LiO t Bu resulted in smooth isomerization into isomers 3a'', 3w'', and 3av'' in yields beyond 80%, albeit with moderate to no E/Z-selectivity.Similar results were obtained when compounds 3ae, 3ag, and 3aj were treated with DBU as a milder base (average yield = 88%, median 92%).Eventually, the latter conditions were combined with the aza-Wacker coupling in a two-step, one-pot sequence to afford vinylated pyrazole 3af'' in 77% yield (Scheme 3b).The synthetic versatility of the aza-Wacker products was further demonstrated in exemplary Dieckmann cyclizations of 3c and 3bg using LiO t Bu as a base, which furnished corresponding cyclopent-2-enones 4a and 4b in 72 and 56% yields, respectively (see the Supporting Information for details).
Exemplarily, we also investigated the possibility of running the allylic aza-Wacker coupling enantioselectively using a set of chiral selenium-π-acid catalysts that were previously shown to provide high levels of stereoinduction in related transformations (Scheme 4; for details, see the Supporting Information).15f, 18,22 For this purpose, alkene 1c was used as the model substrate, which was exposed to chiral catalysts 5a− c under the standard conditions determined in Table 1.Catalysts 5a 22 and 5b 18 furnished product 3c in yields comparable to that of (PhSe) 2 , albeit with low levels of stereoinduction (e.r.= 66:34 and 68:32, respectively).On the contrary, catalyst 5c 15f provided compound 3c in an e.r. of 92:8 on a 0.30 mmol scale, which remained virtually invariant when scaling up to 1.00 mmol.However, in both cases, the Scheme 3. Application of the Intermolecular Aza-Wacker Coupling of Alkenes with Azoles by Photoaerobic Selenium-π-Acid Multicatalysis (a) Late-Stage Functionalization of Biologically Active Compounds and Drug Analogs (b) Sequential and One-Pot Synthesis of N-Vinylated Azoles a a (a) Reactions were carried out on a 1.00 mmol (1.00 equiv) scale with regards to the limiting compound, using 5 mol % TAPT and 10 mol % (PhSe) 2 in DCE (0.2 M) under irradiation at 448 nm at 19 °C.Yields and regioisomeric ratios (r.r.= isomer 3: isomer 3′) refer to isolated compounds.If isomer 3′ was indetectable in the 1 H NMR spectrum, r.r. is given as >49:1.For details, see the Supporting Information.(b) Yields and regioisomeric ratios (r.r.= isomer 3": isomer 3) refer to isolated compounds.If isomer 3 was indetectable in the 1 H NMR spectrum, r.r. is given as >49:1.b Alkene 1 (1.00 equiv), N HetH 2 (3.00 equiv).c (4-ClPhS) 2 (5 mol %) added.d Alkene 1 (3.00 equiv), N HetH 2 (1.00 equiv).e DCE/HFIP = 3:2 used as a solvent.f N 2 :N 1 = 5:1.g 3 (1.00equiv), THF (0.05 M), LiO t Bu (5.00 equiv), 0 °C, N 2 .h 3 (1.00equiv), DCE (0.05 M), DBU (2.00 equiv), r.t., N 2 .i Coupling was conducted under conditions b, followed by solvent exchange in the same vessel to continue the reaction under conditions h.H:Z = Hofmann:Zaitsev elimination ratio.isolated yields did not exceed 30%.A similar outcome was observed with benzotriazole 2f as the coupling partner, furnishing 3bh in 27% yield and an e.r. of 90:10 on a 0.30 mmol scale.The sum of these results clearly shows that the allylic aza-Wacker coupling has indeed the potential to be further developed into an efficient enantioselective process.To reach this promising goal, further reaction optimization remains indispensable and will continue in our laboratories.

■ CONCLUSIONS
In summary, we have presented a novel and operationally simple method for the aza-Wacker coupling of azoles and azinones with alkenes.The reaction proceeds through a radical-polar crossover mechanism, 16 in which a diselane catalyst is sequentially oxidized to an oligomeric selenonium ion by a photoredox catalyst.15b,g, 19 The cationic selenium species functions as a potent π-acid, activating alkenes via seleniranium ion formation.Interception of these ions by azole and azinone nucleophiles, followed by eventual β-elimination, was shown to result in a broad product scope with excellent functional group tolerance.From a regiochemical perspective, our findings complement previous reports on cognate photoredox catalytic aminations of alkenes, as they typically result in the amination of the less substituted position 3 with anti-Markovnikov selectivity (Scheme 1, path d).Our conditions, however, show a preference for position 2 with Markovnikov selectivity in the case of trisubstituted alkenes.Therefore, we are optimiztic that our protocol will find ample application in the realm of organic synthesis and related disciplines as a complementary means to decorate Nheterocycles with carbon residues.Further efforts toward the design of enantioselective versions of our intermolecular aza-Wacker protocol are currently underway in our laboratories.

Table 1 .
Optimization of Photoaerobic Aza-Wacker Coupling of Alkenes with Azoles a